Great. Good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 45th Annual Healthcare Conference. For our next session, very excited to have a fireside chat with NewAmsterdam, and it's my pleasure to introduce Dr. Michael Davidson, NewAmsterdam CEO and co-founder, and Ian Somaiya, Chief Financial Officer. It's a privilege to have you both here. Thanks for joining us, and I figured I'd hand it over to you to start with maybe a State of the Union. You could talk about what was achieved last year and what we have to look forward to this year.
Great. Well, thanks, Tyler. Excited to be here and meeting with the investors, so I just want to go back 12 months ago. We were in the midst of our three pivotal Phase 3 trials, TANDEM, BROOKLYN, and BROADWAY, and they all read out last year towards the end of the year, November through December, and we're excited about the overall profile of the drug. Phase 2 showed us a very efficacious and well-tolerated drug. And we are excited to confirm that the efficacy that we saw in Phase 2 translated to Phase 3, so 33% to 36% monotherapy, LDL lowering, and then 50% with the fixed-dose combination with ezetimibe, which puts us in the most effective LDL-lowering therapy, close, if not better, than the injectable, so very similar to the injectable LDL efficacy.
But it was also, for me, as a clinician, I can speak on behalf of the patients that I see. The biggest factor for a patient's decision about a drug is their safety and tolerability of the medication. And in that sense, obicetrapib far exceeded our expectations. We saw dropout rates lower than placebo, no difference in any of the biochemical parameters, no liver enzyme elevations, no CK elevations, improvements in diabetes measurements, improvements in renal function. So it was extremely well-tolerated. I've never seen a drug in all my years of clinical research, which is more than 30 now, a drug that had this type of safety profile. And so that was quite exciting.
And then we also confirmed in our Phase 3 trial some of the other attributes of the drug, Lp(a) lowering, 35%-40% median reduction consistently across all the trials, reductions in small LDL particles by 90%. And then in the Broadway trial, we saw two very important things that we were hoping to see because we powered Broadway, which is our largest of the Phase 3 trials, to be a very large single trial. We saw improvements in diabetes measurements, which is conversion of prediabetes to diabetes or worsening of glucose control, which is made worse by statins over time. Actually, had improvements with obicetrapib in combination with statins in these studies. And so that, I think, is a very important other attribute.
Then people got really excited, as did we, when we saw that the major adverse cardiac event reduction of 21% for three-point MACE was greater than expected. You wouldn't expect to see much in one year. At best, 0.9. We saw 0.79. And then for both Brooklyn and Broadway, we saw the same reduction in MACE events. So two studies showing that benefit. When we pull the two studies together, using a three-point MACE, which has been used in other trials, especially the Merck anacetrapib trial, it was 0.68 with a P-value of less than 0.05. And then the separation of the curves, which is what you want to see. You want to see that they stay together. And then the Kaplan-Meier curves separate. At six months, we saw this really nice separation, which is very statistically significant.
And so we'll show more of that data as time goes on. But we could not be more thrilled by the drug that we have, obicetrapib, and what it means for ultimately patient treatment and reduction of cardiovascular disease. We're also very gratified by the market itself is changing to the positive. We're seeing more growth in statins. And also branded drugs are growing very significantly because now the guidelines have started to shift back to getting people more to goal, getting LDL levels lower. More and more appreciation of the lower is better is back again as it was a decade ago. And so we hope this will turn the corner because we've seen this marked increase in cardiovascular death over the past decade when those guidelines did shift back away from goals and towards just using statins.
So now we're seeing this, we hope, improvement in death rates now with the reinvigorating LDL targets and lower is better. So it's been an exciting year for us. That was reflected a lot in our value creation for the company. And now this year is going to be more about getting ready to launch the drug and regulatory interactions and more data readouts. We have a lot of data that we need to publish and present in the upcoming meetings for this year. Yeah. Maybe one other thing I would add is from an achievement standpoint is the issuance of new IP. So there was a new composition of matter patent that was issued June-July of last year. And that takes our IP out to 2043 in the U.S. And as you can imagine, that's a patent that we plan to prosecute globally.
Maybe you could just give some brief background on that patent?
Yeah, absolutely. So typically what you find with small molecule drugs is the most stable developable form tends to be the solid form of the drug with the crystalline structure. The unique feature of obicetrapib is the only developable form is the amorphous form. And that observation allowed us to pursue a new patent filing last year. And ultimately, that was issued. So this is an Orange Book-listed patent, composition of matter, and ultimately gives us further extension of the patent life of the drug.
Great. Thanks for that. And Michael, thank you very much for the overview. As you mentioned, the 21.
2043.
Yeah. And as you mentioned, the 21%-32% MACE benefit demonstrated in Broadway at the end of last year was eye-popping, given that it was only 12 months. Obviously, no one was expecting that. I guess as you think about obicetrapib, obviously LDL is one way to achieve a MACE benefit, but it's got a unique mechanism of action. What are the other ways that you believe are contributing to this MACE benefit that you're seeing?
Sure. So we outlined when we talked about it because we are exploring all these different attributes of obicetrapib. The one that I think gets the most attention is the Lp(a) lowering effect because that's obviously a very hot target right now. A lot of folks are developing Lp(a) lowering therapies that are quite effective to lower Lp(a). And so the outcome studies are now underway. So the median reduction of Lp(a) overall, all our trials, is in that 35%-40% range. And so if you translate that into modeling, how you can model that benefit, you'd expect then that we could lower the absolute Lp(a) lowering of roughly 40-50 nanomoles per liter, depending on the baseline levels of Lp(a) with our drug, especially in that higher Lp(a) patient population.
So that should add somewhere between 3%-5%, if not more, relative risk reduction to the LDL benefit of roughly 20% already. So that's one element. I think that's a great approach to the high Lp(a) patient. As a clinician, again, I'm thinking about the patient. And I have somebody, let's say even the Lp(a) therapies are available, and you have an option to start with obicetrapib. You can start there, get their Lp(a) levels down, because it only will be available for those that have the highest level of Lp(a). And they already have to have pre-existing cardiovascular disease. So for those that don't have levels that high, which is about 175, depending on the study, and then existing heart disease, most people don't really qualify then. And it's going to be probably specialty price, so $15,000. So here's a drug that's oral, effective, safe, well-tolerated.
Go with that first, especially if they don't qualify for the injectable drug, so I think it's going to be a really important clinical differentiator as well as a good reason to go to obicetrapib. That's one. The other thing, which I think is potentially even more important, is the small particle reduction of 90% because that just wipes out the small particles, and for someone like myself who's very involved in doing advanced lipid testing, those small particles are what we see all the time in people that have residual cardiovascular risk, and to completely wipe them out with our drug, I think, can really contribute to a more rapid benefit in MACE, so that's the second one, then of course, the diabetes benefit, preventing diabetes or reducing the worsening of glycemic control.
and then even the HDL raising, people dismiss it as being kind of a neutral effect, which is based on certain studies, but the most recent AEGIS-II trial with infusions of HDL that's got published showed an acute benefit within 12 months on reducing certain events like revascularization, and so that's what we saw predominantly in our study. That was the biggest contributor to the overall MACE benefit was revascularization, which makes sense because that's the first thing you prevent when you have somebody with coronary disease. You first stop the revascularization, which is now becoming more and more the important MACE event in these patients, then you stop heart attacks, then you prevent death. We saw across the board all three of those things being beneficial, so I think those are the four things you think about.
And again, what's unique about obicetrapib? It affects all four of those in a very robust way. We hope that'll link up. That confidence we have based on the Broadway and then Broadway-Brooklyn pooled data will translate into PREVAIL, which has almost identical patient population to the Broadway trial. It's really Broadway was designed to be like a mini outcome study on purpose. So now we have that data. We can utilize that study to then hopefully get people more and more confident that PREVAIL will read out positive as well.
We'll get to PREVAIL in a second. But one of the things that stood out when we were doing our work prior to initiation of coverage a while ago was when you look at all these biomarkers, everything's moving in the right direction. It's strange to see, right? Because you don't see that with other therapies. Why do you believe we're seeing that with obicetrapib? Is it related to its mechanism and how the mechanism works? Maybe a brief refresher for the audience.
Yeah, yeah. The mechanism is the key because, again, I was the first one to patent CETP inhibition back in the '90s. So it goes way back. Because when you think about biology, animals that lack CETP, which is the rat, the dog, the mouse, they have very high HDL, very low LDL. Then when you give a mouse transgenically CETP, you make it atherosclerotic sensitive. The dogs don't get atherosclerosis. That was the way it goes. History lesson. Over 100 years ago, cholesterol-fed rabbits got atherosclerosis. That was the first description of atherosclerosis. The predominant model was the dog, Pavlov's dog, that they would have given it to dogs that wouldn't have shown anything. So just by luck, they fed it to rabbits and got athero.
That was kind of forgotten over the years until they discovered it again. Anyway, it's just a fortuitous thing that CETP is very much involved in that atherogenic profile that we have as humans and monkeys and rabbits. We're the ones that are sensitive to atheros. That made it obviously an exciting target to go after. Initially, it was all about HDL raising. The LDL lowering part was not really thought about as a major factor. What we now learned is that, when all the human data and Mendelian randomization, it's the LDL lowering that translates to better reduction in heart disease rates and longevity when you have CETP loss of function. Then the other benefit came from the REVEAL trial with the Merck anacetrapib study. The LDL lowering was what translated to cardiovascular benefit.
The HDL raising did not have a big impact, at least, and so we now focus on the LDL lowering. That's the big shift with our company. The upstream was focusing on the LDL benefit and why that's important for CETP inhibition. But you lower LDL in all the human data. There's humans that don't have any CETP, and their LDL is about 50. And they don't get heart disease. They live longer. So it's a great reference for us that we don't need CETP. And we developed it evolutionary-wise to help conserve cholesterol, to keep it in our body. But now we have plenty of stuff to get cholesterol in. We don't need it. We don't need it anymore.
That's a great question from the audience.
Four drug companies have tried.
Yeah.
Pfizer failed because of high blood pressure. Lilly and Merck because of lower efficacy, and Roche's drug only raised HDL and didn't even lower LDL.
Yeah.
What is so unique about your product where you succeeded while others have failed? In your three Phase 3 studies of 13,000 patients, how much blood pressure increased, if any, at all, did you say?
The first question.
Yeah, the first question is, what about why did the four other ones fail? So I think it was all part of our initial founding of the company five years ago to understand why the four failed. That was an important point.
How did you succeed with it?
The Pfizer one is easy. It was an off-target effect to raise blood pressure. The other ones have not raised blood pressure, and they've been quite safe. So it was just an off-target effect for obicetrapib, which actually you've injected into a mouse, a rat who has no CETP. The blood pressure goes up within seconds. So it induces aldosterone production, had a very toxic off-target effect. So that one's easy to explain. The dalcetrapib, the Roche one, raised HDL like 30%, 40%, a very weak CETP inhibitor, but had no effect on LDL. It was, again, very safe. Didn't show a MACE benefit overall. And then the Lilly one, which is a good drug, it lowered LDL by 15%-20%, raised HDL. But they designed the study for HDL raising.
It only went two years, total duration, which we know was too short to see a benefit for that amount of LDL lowering. Then the Merck one, what's the misconception there? We always hear this all the time. The Merck one failed. It actually worked. It worked. They didn't design it properly for an LDL trial because they looked at 30,000 patients, the largest outcome study done to date. And they focused on HDL raising again, but they did power it for LDL lowering. But the LDL baseline was 60. It lowered LDL to 11 milligrams per deciliter and had a 9% relative risk reduction, which is actually as good, if not better than expected for the amount of LDL lowering. So it did work. And you would expect at 6%, it was 9%. Look at the top third of the patients, which is LDL over 70.
It lowered LDL by 23 milligrams per deciliter, reduced risk by 18%. Again, you would expect at 13%, it was 18%. So the Merck one worked, and it was well tolerated. But the problem was the drug would accumulate in fat tissue. It would not stop accumulating. And it actually crystallized. We did biopsies, fat biopsies. You can see the drug crystals in the fat. So Merck decided after all that not to file the drug for that reason.
How did yours succeed with obicetrapib?
We have a much more potent LDL lowering drug. We have lower LDL. It's twice as good as the other CTP inhibitors, if not more, because of so much better LDL lowering. And we've done a lot of extensive blood pressure monitoring. We have no effect on blood pressure in Phase 3, including a 24-hour, one of the largest 24-hour blood pressure monitoring studies ever done, 200 patients, and no effect on blood pressure on the drug. In fact, blood pressure went down a half a point compared to placebo. So we have no blood pressure issue whatsoever with the drug. And so that, I think, takes that off the table. The other ones, both the anacetrapib and the evacetrapib, they were very well tolerated, and they had good outcome data on mortality. So they were safe.
But they did slightly raise blood pressure at one point, and they did raise CRP, inflammation. Ours, again, lowers blood pressure and does not raise CRP. It will actually lower CRP compared to placebo. So those are little differences that we think those are important for the geeks like us that think about these drug effects. But it's a differentiator. We have a very low-dose, very safe molecule. That's a big difference. And we have double the LDL lowering effect overall.
Maybe the other observation from the other CTP inhibitors was the diabetes benefit. We're not the first in the class to show it. It's actually been quite consistent with the other drugs. The fact is we're seeing it at one year.
Did I miss one more?
Yeah.
We got a question back there. Maybe we'll take it. Yeah, what's your question?
Thank you. I'm sure you get this question a lot. If you could compare your profile with that oral PCSK9, what would you be looking for from the AstraZeneca compound at 18 weeks?
Right. The question is, what about the oral PCSK9s in our profile compared to those? First of all, I'm very happy they're being developed. Again, I put my clinical hat on. I still see patients four days a month. And having more options, oral options in particular, is a fantastic thing for patients. The Merck one, I'll start there. Oral peptide. It's kind of like Rybelsus. Rybelsus is an oral GLP-1. We use it, but it's kind of a challenging therapy to use because you have to take it after eight hours of fast and no other drugs in combination. So you got to plan accordingly for how you because these people are on a lot of other drugs. It lowers LDL based on phase 1, 2 data, 50% or so. We're going to have a similar efficacy with our fixed-dose combination with ezetimibe.
But again, it's all about the other attributes, which is the LDL lowering should be better based on what we know about PCSK9. It does lower LDL a little bit, but not as much as we have with our data. Diabetes benefit is going to be there versus PCSK9. We know that may actually make it a little bit worse over time. And of course, the small particles and so forth. So ours is going to have a better overall profile, in our opinion. But we love the fact that we're going to have another very big marketing muscle in the market to enhance more and more patients getting on therapy.
And if clinicians have a choice between a small little pill that can lower LDL the same or a big peanut-sized M&M pill that has a lot of drug interactions, I think they'll choose our drug, especially when the other benefits are in effect. Now, the AstraZeneca one's further behind, 30%-38% monotherapy benefit in Phase 1b. We'll have to see. I think we're expecting similar data in Phase 2 coming up very soon, the next few weeks. But that's going to be a few years behind us. And they're going to probably need outcome data, I think, to get good traction as well because it's a totally novel mechanism as a disruptor of PCSK9. So we'll see. I think it's also got to look at a lot of factors need to be still evaluated.
Long-term durability, safety, liver toxicity, all that stuff is going to have to be evaluated in these longer-term trials before you come to a competitive landscape with that drug.
Maybe just to answer that specific question you asked in terms of expectations, our expectations are no different than ones that AstraZeneca has communicated, which is Phase 2 data to look similar to their Phase 1, 2 trial.
All right. A lot of questions to knock off and not much time. So we're going to see if we can save the audience questions to the end. But April, you guys have an important decision to make with the PREVAIL outcomes trial. You're going to be looking at the data on a blinded basis, is my understanding, and then deciding whether to use a three or four-point MACE. 32% MACE benefit at 12 months sounds better than 21%. So what is this data going to tell you? What is left to decide?
We're seriously thinking about it, but we also just want to see what the event rates are. And we also want to talk to our academic steering committee and also talk to the regulators. So we got some work to do to get what the next steps might be. But we know for sure we'll be forthcoming with what happens with stroke anyway. And stroke is a tough endpoint to adjudicate because you have embolic stroke, you have hemorrhagic stroke, and you have ischemic stroke. And so you got to figure out, and I do adjudications myself, so I know how hard it is to figure it out sometimes. And so you have to kind of, and that's sometimes making it a little bit of a messier endpoint. But nevertheless, LDL lowering does improve stroke overall over time. So we're heavily considering what to do, let's put it that way.
We want to be thoughtful about it, get the buy-in from everyone before we make a decision.
Yeah. But just so we all appreciate the timing, end of April of 2025 marks the one-year anniversary of the completion of enrollment of PREVAIL, after which we'll review the data, have conversations with our advisors, engage with the FDA. So there should not be an expectation that we'll provide an update other than the trial remains on track.
As we think about MACE benefit in general, the PREVAIL trial is over two and a half years of follow-up, right? And 21%-32% was at 12 months. And how much MACE lowering do you typically see in an outcomes trial in the first year?
At best, about 10%, yeah. So we exceeded expectation, which is our motto. That's the motto of the company, exceed expectations. So expect more. So we feel that the other attributes could have contributed to the benefit. Also, the low dropout rate, all those things factor in how you think about the drug.
But relative to what you would see in the final outcomes data, is it about half that benefit?
That's what you should expect about the first year should be about half of what you see overall. But it starts blending. So you think about how that factors in. Again, we're encouraged by the Kaplan-Meier curve and how it looks and how it behaves. It all fits together to give us more and more confidence that PREVAIL will be successful.
Yeah. So we would have expected a 9% benefit at one year based on LDL. Clearly, we saw a 21%. So it's really the other factors.
Yep, yep. 2x 21%-32% is pretty good as we think about PREVAIL. So the various lipid conferences throughout the year, why should investors be paying attention to these presentations? And what do you plan on presenting that could catch some people's eyes?
We're just getting the particle data now. That'll be hopefully, again, confirmatory of what we've seen already. We haven't released the Lp(a)-lowering data. Again, we want to show consistency across all the trials with median reductions because I think that's the better way to look at it. And then we have more and more outcome data to share, especially the Kaplan-Meier curve separation and how that could translate into this more validation of a true effect. And so we plan on publishing all the trials this year in major journals. We're submitting to major journals, and we'll see what happens. And so I think that, again, people are going to hope to see our data in press, and they can look at it and see how much we've kind of tried to position it the right way for how it should be interpreted.
Yeah. And Tyler, really the thought is you should have even greater confidence in PREVAIL being successful. And we want to give you visibility into the different subpopulations where the drug could be utilized. And when we think about subpopulations, they're still in the millions. So that's really the opportunity for the data releases this year. The one trial we didn't speak to was the Vincent Gogh. So that's a dedicated study in Lp(a) patients where we're evaluating the combination of obicetrapib and Repatha. So if we see just pure additivity or looking at a product, a combination that could provide 50%-60% reduction in Lp(a) in patients that are at risk.
Wonderful. And following on the Lp(a) topic, so the Phase 3 HORIZON trial, pelacarsen was delayed to the first half of 2026. So curious to just get your initial reaction to that delay and what it means for OB and what you hope to see in that trial.
I think my gut feeling tells me it's working. That's why event rates are down, which is great. But for us, it's a really great opportunity. Because if it is working, that's fantastic. That is a win for us. But on the other hand, it's not therapy. All the other benefits are there. So it's not critical, but it's a nice to have. But more importantly, being delayed allows us to potentially launch maybe a year ahead of an Lp(a) -lowering therapy. And I would say as a clinician, I can tell you I think the leading referral to me now is high Lp(a) . And I think patients are self-referral. There's a pent-up demand. And so we'd be the first one on the market to have a pretty robust Lp(a) -lowering benefit.
And so I would say this is going to be something that could help us in our launch. Kind of a lot of people want to be on the drug for that benefit because there's nothing else available for them at that time. So I see that as a real opportunity for us. And that's how we're thinking about the launch timing and how that affects our thinking about that.
What proportion of Lp(a) patients I guess you touched on this earlier a little bit in terms of the cutoff for Horizon, but how do you expect to coexist with the RNAi Lp(a) lowering therapy?
I think it's great for us because they're going to be at that 150. Well, it depends on what study and what inclusion. Let's say 125-175, maybe as high as 200, I think, in mg/dL inclusion with existing heart disease. So all the people that don't yet have heart disease won't qualify for the drug. And a lot of them will know about their Lp(a) levels because they have a strong family history. So it's going to be available. We'll only have obicetrapib available really to give those patients. And then for those that have Lp(a) levels that qualify for the injectables, they may want to try obicetrapib first and then only add on if necessary because it will be specialty priced. And then all the people that have heart disease that don't have Lp(a) levels to that high degree also would not qualify.
So we see the whole Lp(a) lowering class as a huge opportunity for us to have that available for patients.
Yeah. So we spent so much time talking about obicetrapib as a monotherapy, but obviously the fixed dose combo, Tandem data was great. How do you see things playing out once the drug gets approved and you're launching it commercially between the fixed dose combo and the monotherapy?
I think, again, I'm a lower is better kind of guy. I think the combo would be what I would go to primarily for patients. Like ezetimibe is a very, again, safe, well tolerated also. So I would go with the combo predominantly, but we have both. The combo, we want to continue to develop the special combination mechanism of the two drugs together. We've seen that synergy in all our trials. We see it in preclinical studies on athero. So now we're doing the REMBRANDT trial, which is enrolling, which is an imaging, a CT angio plaque analysis to look at plaque reduction over 18 months with the combination versus placebo. And that'll be part of our whole clinical benefit commercial promotion. It is about how the combo has its own unique benefits and could potentially lead to even greater cardiovascular outcome benefits as well.
A final question. Can you just remind us on the timeline to filing in the U.S. market and how that's coordinated with the PREVAIL data and then also a European market introduction and whether you need outcomes for that launch?
Europe is going to be filed this year and launched next year. We met all the criteria for EMA filing. For U.S., we want to. There's a year on the market before you establish a price so that it fits in when PREVAIL reads out. For the U.S., we want to kind of work backwards and say when does PREVAIL finish, you want to try to file so that we have the outcome data in hand at the time of launch. That's how we're thinking about the launch timing.
Okay. Great. We're up on time, but to close out, I'd like to ask you both what you believe is the most underappreciated aspect of the NewAmsterdam story by investors?
Want to go first?
Sure. So I think there's a great appreciation for the know-how that Michael and John bring and the clinical execution, which has been on full display. So hats off to our clinical operations team. I think there also has to be an appreciation for the commercial organization that's being created at NewAmsterdam. We hired B.J. Jones a little over a year and a half ago, and he had tremendous success at Biohaven launching Nurtec into a space that's with many parallels to the market that we're about to enter into. So as Michael says, the company motto is expect more. I think we've delivered more from a clinical standpoint, and that's the plan from a commercial standpoint as well.
I just want to say one more point that I think we don't get valued on is how safe this drug is because at the end of the day, that's what patients care most about, whether it lowers LDL by 40% or 35%. But it's all about how do I feel? I don't want to feel any side effects. And we could not have asked for a better drug in that regard to develop. And so I'm just excited to get that drug to patients and see the response that we get because the patients complain about the statins and all the other drugs. And here we have something that really is so well tolerated. I believe that's going to translate to very great success for patients and for us commercially.
Yeah. Great. Michael, Ian, thank you very much.
Thank you.
Appreciate it.
Thank you, Tyler.